N-substituted-2-amino-4-phenyl-4-oxo-butanoic acid compounds having kynurenine-3-hydroxy base inhibitory activity

ABSTRACT

An N-substituted-2-amino-4-phenyl-4-oxo-butanoic acid compound of the formula (I):                    
     wherein X, Y, W and R are as defined herein.

This application is a 371 of PCT/EP97/04271 filed Jul. 31, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention refers to the use in the prevention and/ortreatment of neurodegenerative diseases, such as, for example,Huntington's chorea, Alzheimer's disease, dementia caused by aquiredimmunodeficiency syndrome (AIDS), infarctual dementia, cerebralischemia, cerebral hypoxia, Parkinson's disease, epilepsy, head andspinal cord injury, amyotrophic lateral sclerosis, glaucoma/retinopathy,infections and inflammations of the brain, ofN-substituted-2-amino-4-phenyl-4-oxo-butanoic acid derivatives which actas inhibitors of kynurenine-3-hydroxylase (KYN-3-OHase), the enzymewhich forms part of the metabolic pathway of kynurenine.

A second object of this invention is directed to a restricted class ofthe above N-substituted-2-amino-4-oxo-4-phenyl-butanoic acid derivativesas novel compounds, either as single enantiomers or as mixture ofenantiomers, to their pharmaceutically acceptable salts, to a processfor their preparation, and to pharmaceutical compositions containingthem.

2. Description of the Background

In the central nervous system (CNS) the metabolism of tryptophan is wellknown to result largely in the production of indolamines such as theneurotransmitter serotonin, while in the periphery most of non-peptidetryptophan utilisation is along the kynurenine pathway, ultimatelyleading to the formation of nicotinamide adenine dinucleotide (NAD)(FIG. 1). The legend to FIG. 1 is to be found on the last page of theexperimental part. In the last decade several lines of evidence havedemonstrated that two intermediates of the kynurenine metabolism,quinolinic acid (QUIN) and kynurenic acid (KYNA), when injected in theCNS, act as a neurotoxin and as a neuroprotectant, respectively.Consequently, the demonstration that these two metabolites of thekynurenine pathway (unable to cross the blood brain barrier), are normalconstituents of the mammalian brain, has suggested the existence of thispathway within the CNS and proposed the involvement of QUIN and KYNA inbrain physiology and pathology (Stone T. W., Pharmacol. Rew., (1993),310-379). Both QUIN and KYNA are able to interact with the ionotropicexcitatory amino acid receptors. In particular, QUIN is a highlyselective agonist at N-methyl-D-aspartate (NMDA) receptor (Stone T. W.,Eur. J. Pharmacol., 72, (1981) 411-412), whereas KYNA is a broadspectrum antagonist of the ionotropic excitatory aminoacid receptors,preferentially acting at the glycine co-agonist site of the NMDAreceptor (J. Neurochem., 52, (1989) 1319-1328). In vitro studies havedemonstrated that the exposure of neuronal cell cultures to relativelylow QUIN concentrations are neurotoxic either when applied over aprolonged period of time or in combination with glutamate (Schurr A.,Brain Res., 568, (1991) 199-204). In vivo QUIN has been shown to produceconvulsions and axon sparing lesions that mimic the nerve cell lossdescribed in human neurodegenerative disorders (Schwarcz R., Science,219, (1983) 316-318). Moreover an increase in QUIN production has beendemonstrated in post-ischemic gerbil brain (Saito K., J. Neurochem., 60,(1993) 180-192), following spinal cord trauma in rats (Stokes B. T.,Brain Res., 633, (1994) 348-352) and in guinea pig (Blight A. R., BrainRes., 632, (1993) 314-316), and, finally, in a model of experimentalallergic encephalomyelitis (Flagan E. M., J. Neurochem., 64, (1995)1192-1196). On the other hand, KYNA has shown anticonvulsant andneuroprotective properties in several animal models (Stone T. W.Pharmacol.Rev.45,(1993) 309-379), and, additionally, theexperimentally-evoked rise of KYNA concentrations is capable to elicitneuroprotection and seizures reduction (Nozaki K., J. Cereb. Blood FlowMetab., (1992), 12, 400-407; Russi P., J. Neurochem., 59, (1992) 2076).Notably, KYNA when co-injected with QUIN is able to prevent theexcitotoxic neuronal damage evoked by the neurotoxin (Foster A. C.,Neurosci. Lett., 48, (1984) 273-278). These data taken together suggestthat KYNA may act as the brain's own defence against detrimental events,such as excitotoxicity and seizures, leading to pathological situations(Schwarcz R., Neurotoxin and neurodegenerative disease, Ann. N.Y.Sci.,140, vol. 648, 1992). It follows that pharmacological interventionsaimed at increasing KYNA formation and/or blocking QUIN synthesis can beuseful in the treatment of excitotoxic brain diseases. In the Kynureninepathway (see FIG. 1), KYN-3-OHase is the first enzyme involved in theformation of QUIN from kynurenine. Pharmacological agents acting asinhibitors of this enzyme able to block the metabolism toward QUIN and,at the same time, to increase KYNA formation, can be useful asneuroprotective agents in the prevention and/or treatment of all theneurodegenerative pathologies involving quinolinic acid or excessiveactivation of neurotransmission mediated by excitatory amino acid (EAA)receptors.

There is therefore a need to find pharmacological substances which canbe useful as neuroprotective agents by means of their activity asinhibitors of the enzyme KYN-3-OHase. The present invention fulfillssuch a need.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides aN-substituted-2-amino-4-phenyl-4-oxo-butanoic acid compound of formula(I)

wherein

each of the groups X and Y is, independently, hydrogen; halogen; nitro;C₁-C₆ alkyl; C₂-C₄ alkenyl; C₂-C₄ alkynyl; C₁-C₆ alkoxy; C₁-C₆alkylthio; SOR₂ or SO₂R₂ in which R₂ is C₁-C₆ alkyl, phenyl or benzyl;or SO₂N(R₃)₂ in which each of the groups R₃ is, independently, hydrogen,C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, phenyl or benzyl;

R is hydroxy; —OR₅ in which R₅ is C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl or benzyl; —N(R₃)₂ or —N(R₃)OR₃ in which each of R₃ is asdefined above;

w is —COOR₄, —COR₄ or —SO₂R₄ in which R₄ is C₁-C₆ alkyl, an optionallysubstituted C₂-C₄ alkenyl, an optionally substituted phenyl or benzyl;—CONHR₅ or —CSNHR₅ in which R₅ is as defined above; trichloroacetyl; ortrifluoroacetyl; and the pharmaceutically acceptable salts thereof, foruse as a medicament, in particular as Kynurenine 3-hydroxylaseinhibitors.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A preferred class of compounds of formula (I) are those wherein

each of the groups X and Y is, independently, hydrogen; halogen; nitro;C₁-C₆ alkyl; C₁-C₆ alkoxy; C₁-C₆ alkylthio; SOR₂ or SO₂R₂ in which R₂ isC₁-C₆ alkyl, phenyl or benzyl; SO₂N(R₃)₂ in which each of the groups R₃is, independently, hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,optionally substituted phenyl or benzyl;

R is hydroxy;

W is —COOR₄, —COR₄ or —SO₂R₄ in which R₄ is C₁-C₆ alkyl, an optionallysubstituted C₂-C₄ alkenyl, an optionally substituted phenyl or benzyl,trichloroacetyl or trifluoroacetyl; and the pharmaceutically acceptablesalts thereof.

Examples of specific compounds of formula (I) are the following:

N-methylsulfonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′-chlorophenyl)-butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′-fluorophenyl)-butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)-butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-difluorophenyl)-butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′-chloro-4′-methoxyphenyl)-butanoicacid;

N-acetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′-fluoro-4′-methoxyphenyl)-butanoicacid;

N-benzoyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)-butanoic acid;

N-methoxycarbonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)-butanoic acid;

N-benzyloxycarbonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)-butanoicacid; either as single enantiomers or as mixture of enantiomers and thepharmaceutically acceptable salts thereof.

The following compounds of formula (I) either as single enantiomers oras a mixture thereof, and the pharmaceutically acceptable salts thereofare novel compounds and are a further object of this invention:

N-methylsulfonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′-chlorophenyl)-butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′-fluorophenyl)-butanoic acid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′-chloro-4′-methoxyphenyl)-butanoicacid;

N-trifluoroacetyl-2-amino-4-oxo-4-(3′-fluoro-4′-methoxyphenyl)-butanoicacid;

N-benzoyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)-butanoic acid;

N-methoxycarbonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)-butanoic acid;and

N-benzyloxycarbonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)-butanoicacid.

The present invention also refers to a selected class of compounds offormula (I) which are novel compounds. Accordingly, a further object ofthe invention, is a compound of the following formula (Ia)

wherein

each of the groups X and Y is, independently, hydrogen; halogen; nitro;C₁-C₆ alkyl; C₂-C₄ alkenyl; C₂-C₄ alkynyl; C₁-C₆ alkoxy; C₁-C₆alkylthio; SOR₂ or SO₂R₂ in which R₂ is C₁-C₆ alkyl, phenyl or benzyl;or SO₂N(R₃)₂ in which each of the groups R₃ is, independently, hydrogen,C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, phenyl or benzyl;

R is hydroxy; —OR₅ in which R₅ is C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl or benzyl; —N(R₃)₂ or —N(R₃)OR₃ in which each of R₃ is asdefined above;

W is —SO₂R₄ in which R₄ is C₁-C₆ alkyl, an optionally substituted C₂-C₄alkenyl, an optionally substituted phenyl or benzyl; —CONHR₅ or —CSNHR₅in which R₅ is as defined above; and the pharmaceutically acceptablesalts thereof.

Preferred compounds of formula (Ia) are those wherein W is SO₂R₄ inwhich R₄ is C₁-C₄ alkyl and X and Y, which may be the same or differentare hydrogen or halogen.

A preferred example of a compound of formula (Ia) isN-methylsulphonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoic acid,either as single enantiomer or as a mixture thereof, and thepharmaceutically acceptable salts thereof.

With reference to formula (I) and (Ia), the preferred meanings of thevarious substituents are as follows.

The alkyl and alkoxy groups may be branched or straight groups.

Representative examples of a C₁-C₆ alkyl group include methyl, ethyl, n-and iso-propyl, n-, iso-, sec- and tert-butyl.

Representative examples of a C₁-C₆ alkoxy group include methoxy andethoxy.

Representative examples of a C₁-C₆ alkylthio group include methylthio,ethylthio and isopropylthio.

Representative examples of a C₂-C₄ alkenyl group include ethenyl,1-propenyl and 2-propenyl.

Representative examples of a C₂-C₄ alkynyl group include ethinyl,1-propinyl and 2-propinyl.

A substituted phenyl or benzyl ring is, preferably, a methoxy, a halogenor a nitro substituted phenyl or benzyl ring.

Halogen includes fluoro, bromo, chloro and iodo; in particular fluoro orchloro.

The compounds of formula (I) or (Ia) have an asymmetric carbon atom and,for this reason, they can exist either as a mixture of optical isomers(enantiomeric mixture) or as single optical isomer (enantiomer). Thepresent invention includes within its scope all the possible isomers andtheir mixtures and both the metabolites and the pharmaceuticallyaccebtable bioprecursors (otherwise known as pro-drugs) of the compoundsof formula (I) or (Ia).

The pharmaceutically acceptable salts of the compounds of formula (I) or(Ia) include the salts of inorganic bases, for example hydroxides ofalkali metals, e.g. sodium or potassium, or alkaline-heart metals, e.g.calcium or magnesium, and the salts of organic bases such as, forexample, aliphatic amines, e.g., methyl amine, ethyl amine or diethylamine, or heterocyclic amines, e.g. piperidine.

The novel and known compounds of formula (I), the novel chemicalentities of formula (I) and the selected class of formula (Ia) included,and the pharmaceutically acceptable salts thereof are therein defined as“the compounds of the invention” and as “the active compounds of theinvention”.

Object of the invention is also to provide the use of a compound of theinvention in the manufacture of a medicament for use askynurenine-3-hydroxylase inhibitor.

The invention also provides a method of inhibitingkynurenine-3-hydroxylase enzyme in a mammal, including humans, in needof such inhibition, comprising administering to the mammal akynurenine-3-hydroxylase enzyme-inhibiting effective amount of acompound of the invention or a pharmaceutically acceptable salt thereof.

Most of compounds of the present invention, either as racemic mixture oras pure enantiomers may be prepared in a single step process, followingthe same procedure described from page 19, line 9, to page 22, of theInternational Patent Application PCT/WO 95/03271, which is reported inthe following Scheme 1.

In the above Scheme 1:

X and Y are, each independently, hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy or C₁-C₆ alkylthio;

R is hydroxy; and

W is —COOR₄ or COR₄ in which R₄ is C₁-C₆ alkyl, an optionallysubstituted phenyl or benzyl, or trifluoroacetyl.

A compound of formula (I), obtained following the above procedure, canbe converted into another compound of formula (I) in which R is otherthan hydroxy, according to known methods.

The reaction of a compound of formula (II) with a compound of formula(III), as decribed in Scheme 1, can be carried out according to knownmethods (e.g. J. E. Norlander, J.Org. Chem., 50, 3619-22, 1985; D. G.Melillo, J.Org. Chem., 52, 5143-50, 1987).

For example, the reaction can be performed in the presence of a suitableLewis acid catalyst, in an inert solvent such as, e.g. dichloromethaneor 1,2-dichloroethane, or in an appropriate aromatic hydrocarbon suchas, e.g. chlorobenzene, nitrobenzene or in an excess of compound offormula (II) itself; at a temperature ranging from about −10° C. toabout 100° C., optionally in the presence of a suitable co-solvent, e.g.nitromethane. A suitable Lewis acid may be, for example, anhydrousaluminium trichloride, anhydrous tin dichloride, titanium tetrachlorideor anhydrous zinc dichloride, typically anhydrous aluminium trichloride.

The compounds of formula (II) are known compounds.

The compounds of formula (III) are known compounds or can be prepared byknown procedures from known compounds.

Alternatively, a compound of formula (I) or (Ia) can be obtainedaccording to the following Scheme 2.

In the above Scheme 2:

each of the groups X and Y is, independently, hydrogen; halogen; nitro;C₁-C₆ alkyl; C₂-C₄ alkenyl; C₂-C₄ alkynyl; C₁-C₆ alkoxy; C₁-C₆alkylthio; SOR₂ or SO₂R₂ in which R₂ is C₁-C₆ alkyl, phenyl or benzyl;or SO₂N(R₃)₂ in which each of the groups R₃ is, independently, hydrogen,C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, phenyl or benzyl;

R is hydroxy; —OR₅ in which R₅ is C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl or benzyl; —N(R₃)₂ or —N(R₃)OR₃ in which each of R₃ is asdefined above;

Q is hydroxy; halogen; R₄COO— in which R₄ is C₁-C₆ alkyl, an optionallysubstituted C₂-C₄ alkenyl, an optionally substituted phenyl or benzyl;trichloroacetoxy; or trifluoroacetoxy; and

W is —COOR₄, —COR₄ or —SO₂R₄ in which R₄ is as defined above; —CONHR₅ or—CSNHR₅ in which R₅ is as defined above; trichloroacetyl; ortrifluoroacetyl.

The compounds of formula (IV) are either known compounds or can beprepared according to known methods from known compounds.

The compounds of formula (V) are commercially available compounds orprepared from commercially available compounds using known methods.

The reaction of a compound of formula (IV) with a compound of formula(V), as decribed in Scheme 2, can be carried out according to methodswell known in the art; for example, those usually employed in thesynthesis of N-protected aminoacid or of peptides. More in detail, acompound of formula (IV) may be reacted with an acid chloride of formula(V) in the presence of an organic or inorganic base, in a customaryorganic solvent such as, for example, dichloromethane, tetrahydrofuranor an excess of the base itself (e.g. pyridine).

Other examples of suitable organic bases are triethylamine andN-methylmorpholine, examples of inorganic bases are sodium or potassiumcarbonate or bicarbonate, in this last case the reaction may be carriedout in a two phases system using, if desired, a phase transfer catalyst.The reaction temperature may range from room temperature to about −40°C.

Alternatively, the reaction may be carried out in water using classicalSchotten-Bauman conditions at temperature ranging from about 0° C. toroom temperature.

A compound of formula (IV) may be reacted with an acid anhydride offormula (V).

A compound of formula (IV) may be reacted with an acid of formula (V)via an intermediate derivative thereof, which can be isolated or not. Anintermediate derivative may be an active ester, e.g. a nitro-phenylester or an N-hydroxysuccinimide ester, a mixed anhydride, e.g. anethoxycarbonyl or iso-butyloxycarbonyl anhydride, or a reactiveintermediate obtained “in situ” by reaction of the acid withdiciclohexylcarbodiimide or carbonyl diimidazole.

For example, an acid of formula (V) and a compound of formula (IV)wherein R is —OR₅, —N(R₃)₂ or —N(R₃)OR₃ in which R₅ and R₃ are asdefined above, may be reacted with dicyclohexylcarbodiimide, if desired,in the presence of a suitable catalyst (e.g. dimethylaminopyridine orN-hydroxybenzotriazole), in an organic solvent (e.g. dichloromethane),at a temperature ranging from about 0° C. to room temperature.

A compound of formula (I) or (Ia) which contains a free carboxy group,namely a compound of formula (I) or (Ia) in which R is hydroxy, can beconverted into another compound of formula (I) or (Ia) in which R isother than hydroxy. This conversion may be carried out according to wellknown methods. For example, a compound of formula (I) or (Ia) wherein Ris hydroxy, can be converted into another compound of formula (I) or(Ia) wherein R is —OR₅ in which R₅ is as defined above, by usualesterification methods, for example, following the procedure describedin: E. Haslam, Tetrahedron, 36, 2409-2433 (1980). Preferably, such anesterification reaction can be carried out via a reactive derivativeintermediate of the carboxylic acid , which may be isolated or not, byreaction with the appropriate alcohol of formula R₅OH in which R₅ is asdefined above. The reaction can be carried out in a customary solvent,e.g. dichloromethane, tetrahydrofuran , toluene, or in the presence ofan excess of the alcohol itself of formula R₅OH, at a temperature whichmay range from about −20° C. to about 50° C. Intermediate reactivederivatives of the carboxylic acid may be, for example, acid halides,e.g. chloride, mixed anhydrides, e.g. etoxycarbonyl or tert-butyloxyanhydride, or a suitable reactive intermediate obtained “in situ”, forexample, by reaction with a diimide, e.g. dicychloexylcarbodiimide orcarbonyl diimidazole.

The esterification reaction may be also carried out by treatment of acompound of formula (I) or (Ia) in which R is hydroxy, with a suitablealkylating agent of formula R₅—L in which R₅ is as defined above and Lis an appropriate leaving group such as, e.g. a halogen atom, preferablyiodine, or a sulfate ester, in the presence of an inorganic base, e.g.potassium carbonate or bicarbonate, or in the presence of an organicbase, e.g. 1,8-diazabicyco[5.4.0]-undec-7-ene(1,5-5) (DBU), in asuitable solvent, e.g. dimethylformamide, at a reaction temperature thatmay range from about 0° C. to about 60° C.

Furthermore, a compound of formula (I) or (Ia) wherein R is hydroxy, canbe converted into a corresponding compound of formula (I) or (Ia)wherein R is —N(R₃)₂ or —N(R₃)OR₃ werein R₃ is, independently, hydrogen,benzyl or C₁-C₆ alkyl, according to known methods; preferably, via anintermediate reactive derivative thereof, which can be isolated or not.Intermediate derivatives may be active esters, e.g., NO₂-phenyl estersor N-hydroxysuccinimide esters, acid halides preferably chlorides, mixedanhydrides, e.g. ethoxycarbonyl or iso-butyloxycarbonyl anhydrides, orreactive intermediates obtained “in situ” by reaction of the acid withdiciclohexylcarbodiimide or carbonyl diimidazole.

For example, a reactive intermediate as defined above, which can beobtained following conventional ways, is reacted with ammonia or anappropriate amine HN(R₆)₂ or an appropriate hydroxylamine or protectedhydroxylamine of formula HNO—R₇ wherein R₇ is a suitable C₁-C₆ alkyl orbenzyl substituent or protecting group; in this last case, R₇ ispreferably a benzyl or trialkylsilyl group. The reaction solvent may bea customary solvent, such as e.g., dichloromethane, tetrahydrofuran,dioxane or an excess of the amine itself, and the reaction temperaturemay range from about −20° C. to about 50° C.

The optional salification of a compound of formula (I) or (Ia) as wellas the conversion of a salt into the corresponding free compound and theseparation of a mixture of isomers into the single isomer, may becarried out by usual methods.

For example, the separation of a mixture of regioisomers obtained asdescribed in Scheme 1, into the single isomer may be carried out byconventional methods. Particularly, the separation of regioisomers maybe carried out by fractional crystallization from a suitable solvent orby chromatography, either flash column chromatography or high pressureliquid chromatography.

As previously described, the compounds of formula (I) or (Ia) can existas enantiomers; the separation of the racemic compounds of formula (I)or (Ia) into the corresponding pure enantiomers can be carried outaccording to techniques and procedures well known in the art; forexample, either high pressure liquid chromatography on a chiralstationary phase, or resolution via diastereoisomeric salt formation ofa compound of formula (I) or (Ia) wherein R is hydroxy, with a suitableoptically active organic base, e.g., phenylethylamine, ephedrine orbrucine, and subsequent separation of the pure diastereoisomeric salt byselective recrystallisation.

It is understood that the preparation of the compounds of formula (I),according to the methods described above, comprises the preparation ofthe compounds of formula (Ia) which represent a selected class ofcompounds of formula (I).

Pharmacology

As already said, the compounds of the invention are active askynurenine-3-hydroxylase inhibitors.

The efficacy of the compounds of the invention in the inhibition of theenzyme kynurenine-3-hydroxylase has been evaluated in rat brainhomogenate, determining the conversion of L-kynurenine toL-3-hydroxy-kynurenine according to the method described below.

(A) Kynurenine-3-hydroxylase assay in the rat brain

Brain was homogenized in ice-cold 0.32 M sucrose and centrifuged at12000×g for 30 min at 4° C. The pellet was washed three times with 0.32M sucrose by centrifugation and suspended in 0.14 M KCl in 20 mMK-phosphate buffer at pH 7 (1 g tissue in 2 ml buffer).

The reaction mixture contained: 75 μl of suspended homogenate; 100 μl ofsubstrate solution containing 50 mM K-phosphate buffer pH 7.5, 2 mMMgCl₂, 0.4 mM NADPH and 50 μM L-kynurenine (final concentration): 25 μlof different concentrations of inhibitor solutions). The reaction wasstopped by addition of 200 μl of 1 M HClO₄ after 60 min incubation.L-3-hydroxykynurenine formed was quantified by HPLC with coulometricdetection at a working voltage of +0.2 V. The column was a 10 cm C₁₈reversed phase (3 μm. The mobile phase consisted of 950 ml distilledwater, 20 ml acetonitrile, 9 ml triethylamine, 5.9 ml phosphoric acid,100 mg sodium EDTA and 1.5 g heptanesulfonic acid. The flow rate was 1ml/min.

As an example, the compounds of the present invention:

(R,S)-N-trifluoroacetyl-2-amino-4-(3′,4′-dichlorophenyl)-4-oxo-butanoicacid (FCE 29256*);

(S)-N-trifluoroacetyl-2-amino-4-(3′,4′-dichlorophenyl)-4-oxo-butanoicacid (FCE 29435*); and

(R,S)-N-trifluoroacetyl-2-amino-4-(3′,4′-difluorophenyl)-4-oxo-butanoicacid (FCE 29434*);

(* means “Internal Code”)

have been tested according to the Method (A) described above.

The obtained results, are reported in the following Table 1.

TABLE 1 Enzyme Inhibition: (Rat brain) Compound IC 50 (μM) FCE 292560.14 FCE 29435 0.24 FCE 29434 0.27

The tested compounds, which are representative of the compounds of theinvention, were found to be significantly active in inhibiting theenzyme kynurenine-3-hydroxylase.

The compounds of the invention are therefore useful in preventing ortreating a disease state in mammals, including humans, whereininhibition of kynurenine-3-hydroxylase is needed.

In particular, the compounds of the invention can be useful asneuroprotective agents in the prevention and/or treatment of aneurodegenerative disease which comprises: Huntington's chorea,Alzheimer's disease, dementia caused by aquired immunodeficiencysyndrome (AIDS), infarctual dementia, cerebral ischemia, cerebralhypoxia, Parkinson's disease, epilepsy, head and spinal cord injury,amyotrophic lateral sclerosis, glaucoma/retinopathy, infections andinflammation of the brain.

The compounds of the present invention can be administered in a varietyof dosage forms, e.g. orally, in the form of tablets, capsules, sugar orfilm coated tablets, liquid solutions or suspensions; rectally, in theform of suppositories; parenterally, e.g. intramuscolarly or byintravenous injection or infusion.

The dosage level suitable for administration to adult humans depends onthe age, weight, conditions of the patient and on the administrationroute; for example, the dosage adopted for oral administration for thecompounds of the invention may range from about 10 to about 500 mg prodose, from 1 to 5 times daily.

The present invention also provides pharmaceutical compositionscomprising a compound of the invention as an active ingredient inassociation with a pharmaceutically acceptable excipient (which can be acarrier or a diluent).

Furthermore, the present invention provides pharmaceutical compositionscomprising a compound of the invention, as an active ingredient, inassociation with a pharmaceutically acceptable excipient (which can be acarrier or a diluent) for use as kynurenine 3-hydroxylase inhibitor.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g. lactose, dextrose, saccharose, sucrose,cellulose, corn starch or potato starch; lubricants, e.g. silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g. starches, arabic gum, gelatin,methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone;disaggregating agents, e.g. a starch, alginic acid, alginates or sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents such as lecithin, polysorbates, laurylsulphates; and, in general,non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. Said pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be e.g. syrups,emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol.

The suspensions and the emulsions may contain as carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethyl-cellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscolar injections may contain,together with the active compound, a pharmaceutically acceptablecarrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g.propylene glycol, and, if desidered, a suitable amount of lidocainehydrochloride. The solutions for intravenous injections or infusions maycontain as carrier, for example, sterile water or preferably they may bein the form of sterile, acqueous, isotonic saline solutions.

The suppositories may contain together with the active compound apharmaceutically acceptable carrier, e.g. cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

The following examples illustrate but do not limit the invention:

EXAMPLE 1(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoicacid. (FCE 29256)

To 1,2-dichlorobenzene (60 ml ; 0.53 mol),(R,S)-N-trifluoroacetylaspartic anhydride (20 g ; 0.09 mol) was added inone portion, under dry nitrogen atmosphere at room temperature. To theresulting well stirred suspension, anhydrous aluminium trichloride (36g.; 0.27 mol) was slowly added portionwise, under dry nitrogenatmosphere, maintaining the temperature below 10° C. The so obtaineddeep-red solution was stirred at 60° C. for 4 hrs, then cooled at roomtemperature.

To the resulting reaction mixture, 6N aqueous hydrochloric acid wasslowly dropped in, maintaining the temperature below 30° C. on cooling.The so obtained yellow suspension was poured into ice/water (200 g/200ml), and hexane (200 ml) was added. The resulting suspension was stirred30 min., then filtered to provide the crude reaction product as slightlyyellow solid, which was washed with water and then with hexane, theresulting solid was then dried in a vacuum oven at 50° C.

Recrystallisation from hexane/ethyl ether afforded the pure titledcompound as colourless prisms (22 g; 68%), m.p. 172-173° C.

¹H-NMR (200 MHz ; d₆-DMSO) ppm: 3.60 (d, 2H); 4.78 (d, 1H); 7.79 (d,1H); 7.90 (dd, 1H); 8.18 (d, 1H); 9.70 (d, 1H), 13.20 (broad s, 1H).

MS (EI; m/z): 357 (M⁺; 2.5), 304 (12), 173 (100)

Microanalysis: calcd. for C₁₂H₈ Cl₂F₃NO₄: C 40.26 ; H 2.23; N 3.91; Cl19.83.

found: 39.53; 2.41; 3.79; Cl 20.17.

Analogously starting from (R,S)-N-trifluoacetylaspartic anhydride thefollowing compounds were obtained:

(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-difluorophenyl)butanoicacid, (FCE 29434), m.p. 159-160° C.

¹H-NMR (200 MHz; d₆-DMSO) ppm: 3.58 (d, 2H); 4.78 (m, 1H); 7.60-8.10 (m,3H); 9.70 (d, 1H), 13.20 (broad s, 1H)

MS (EI; m/z): 325 (M⁺; 4.5), 307 (55.3), 210 (50), 141 (100)

Microanalysis: calcd. for C₁₂H₈F₅NO₄: C 44.35; H 2.45; N 4.35.

found: 44.52; 2.61; 4.08

(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′-chloro-4′-methoxyphenyl)butanoicacid, (FCE 29573), m.p. 164-65° C.

¹H-NMR (200 MHz; d₆-DMSO) ppm: 3.58 (m, 2H); 3.96 (s, 3H); 4.78 (m, 1H);7.30 (d, 1H); 7.98 (d, 1H); 8.0 (s, 1H); 9.70 (d, 1H); 13.10 (broad s,1H)

MS (EI; m/z): 353.1 (M⁺; 5), 169.0 (100)

Microanalysis: calcd. for C₁₃H₁₁ClF₃NO₅: C 44.16; H 3.13; N 3.96; Cl10.04.

found: 44.15; 3.22; 3.92; 9.41.

(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′-fluoro-4′-methoxyphenyl)butanoicacid, (FCE 29574), m.p. 177-78° C.

¹H-NMR (200 MHz; d₆-DMSO) ppm: 3.53 (m, 2H); 3.92 (s, 3H); 4.78 (m, 1H);7.30 (t, 1H); 7.72-7.83 (m, 2H); 9.68 (d, 1H); 13.10 (s, 1H)

MS (EI; m/z): 319.0 (8), 153.0 (100)

Microanalysis: calcd. for C₁₃H₁₁F₄NO₅: C 46.29 ; H 3.29; N 4.15.

found: 46.52; 3.44; 4.08.

EXAMPLE 2(S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoicacid (FCE 29435)

To 1,2-dichlorobenzene (60 ml; 0.53 mol), (S)-N-trifluoroacetylasparticanhydride (20 g; 0.09 mol) was added in one portion, under dry nitrogenatmosphere at room temperature. To the resulting well stirredsuspension, anhydrous aluminium trichloride (36 g.; 0.27 mol) was slowlyadded portionwise, under dry nitrogen atmosphere, maintaining thetemperature below 10° C. The so obtained deep-red solution was stirredat 50° C. for 6 hrs, then cooled at room temperature.

To the resulting reaction mixture, 6N aqueous hydrochloric acid wasslowly dropped in, maintaining the temperature below 30° C. on cooling.The so obtained yellow suspension was poured into ice/water (200 g/200ml), and hexane (200 ml) was added. The resulting suspension was stirred30 min., then filtered to provide the crude reaction product as slightlyyellow solid, which is washed with water and then with hexane, theresulting solid was then dried in a vacuum oven at 50° C.

Recrystallisation from hexane/ethyl ether afforded the pure titledcompound as colourless prisms (20 g; 56%), m.p. 154° C.

[α]_(D)=+16.27° (c=1; abs EtOH)

¹H-NMR (200 MHz; d₆-DMSO) ppm: 3.60 (d, 2H); 4.78 (d, 1H); 7.79 (d, 1H);7.90 (dd, 1H); 8.18 (d, 1H); 9.70 (d, 1H), 13.20 (broad s, 1H).

MS (EI; m/z): 357 (M⁺; 2.5), 304 (12), 173 (100)

Microanalysis: calcd. for C₁₂H₈Cl₂F₃NO₄: C 40.26; H 2.23; N 3.91; Cl19.83.

found: 40.66; 2.38; 3.72; Cl 19.68.

Analogously(R)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoicacid was obtained starting from (R)-N-trifluoacetylaspartic anhydride.

m.p. 154° C.

[α]_(D)=−15.1° (c=1; abs. EtOH)

Microanalysis: calcd. for C₁₂H₈ Cl₂F₃NO₄: C 40.26; H 2.23; N 3.91; Cl19.83.

found: 40.38; 2.80; 3.22; Cl 18.91.

Analogously starting from the corresponding homochiralN-trifluoacetylaspartic anhydride the following compounds were obtained:

(S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-difluorophenyl)butanoicacid (FCE 29571); colourless prisms, m.p. 136-137° C.

[α]_(D)=+9.79° (c=0.9; 95% EtOH)

¹H-NMR (200 MHz; d₆DMSO, ppm): 3.58 (d, 2H); 4.78 (m, 1H); 7.60-8.10 (m,3H); 9.70 (d, 1H), 13.10 (broad s, 1H)

MS (EI): 325 (M⁺), 141.0 (100)

Microanalysis: calcd. for C₁₂H₈F₅NO₄: C 44.35; H 2.45; N 4.35.

found: 44.20; 2.43; 4.34

(R)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-difluorophenyl)butanoicacid, (FCE 29572), m.p. 136-137° C.

[α]_(D)=−11.4° (c=0.7; 95% EtOH)

Microanalysis: calcd. for C₁₂H₈F₅NO₄: C 44.35; H 2.45; N 4.35.

found: 44.43; 2.55; 4.29

EXAMPLE 3(R,S)-N-benzyloxycarbonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoicacid (FCE 29436)

To an ice cooled suspension of(R,S)-2-amino-4-oxo-4-(3′,4′-dichlorophenyl) butanoic acid hydrochloride(10 g, 33.5 mmol), in water (70 ml), 1N sodium hydroxyde (70 ml, 70mmol) was dropped in under vigorous stirring. To the resulting solutionbenzylchloroformate (6.5 ml, 43.5 mmol) and 2N aqueous sodium hydroxyde(23 ml, 46 mmol) were slowly added, from two different dropping funnels,maintaining the reaction temperature below 5° C. The resulting reactionmixture was then stirred at room temperature for two hours, during thistime a colourless solid slowly precipitated.

Then the reaction mixture was cooled at 0° C., and on stirring, 2Naqueous hydrochloric acid was slowly added until the pH of the reactionmixture was 2.

The resulting colourless solid was filtered, washed with water and thenwith hexane, and dried in a vacuum-oven at 60° C.

Recrystallisation of this crude material from ethyl eter/hexane affordedthe pure titled compound as colourless prisms (9.5 g, 72% yield),melting at 141-142° C.

¹H-NMR (200 MHz; d₆-DMSO) ppm: 3.43 (d, 1H); 4.50 (q, 1H); 5.0 (s, 2H);7.30 (s, 5H); 7.58 (d, 1H); 7.67-7.90 (m, 2H); 8.10 (s, 1H); 12.80(broad s, 1H)

MS (FAB⁺; m/z): 396.2 (30); 352.2 (18); 217.4 (100).

Microanalysis: calcd. for C₁₈H₁₅Cl₂NO₅: C 54.56; H 3.8; N 3.54; Cl17.89.

found: 54.68; 3.83; 3.52; 17.97

Using the same procedure the following compounds were obtained:

(R,S)-N-methoxycarbonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoicacid (FCE 29593), m.p. 178-180° C.

¹H-NMR (200 MHz; d₆-DMSO) ppm: 3.42 (d, 2H); 3.56 (s, 3H); 4.50 (q, 1H);7.43 (d, 1H); 7.80 (d, 1H); 7.92 (dd, 1H), 8.18 (d, 1H); 12.80 (broad s,1H)

MS (EI; m/z): 319.0 (2); 301.0 (8); 200 (16); 173.0 (100).

Microanalysis: calcd. for C₁₂H₁₀Cl₂NO₅: C 45.02; H 3.46; N 4.38; Cl22.15.

found: 45.06; 3.58; 4.29; 21.95.

(R,S)-N-acetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoic acid (FCE29585), Was obtained with the above reported procedure usingNa₂CO₃-NaHCO₃ buffer instead of NaOH; m.p. 199-203° C. (a firstsolid-liqid transition was detected by DSC at 190-194° C.).

¹H-NMR (200 MHz; d₆-DMSO) ppm: 1.80 (s, 3H); 3.42 (d, 2H); 4.65 (q, 1H);7.79 (d, 1H); 7.90 (d, 1H); 8.13 (s, 1H); 8.16 (d, 1H); 12.65 (broad s,1H)

Microanalysis: calcd. for C₁₂H₁₀Cl₂NO₄: C 47.39; H 3.65; N 4.61; Cl23.32.

found: 47.38; 3.68; 4.54; 23.21.

(R,S)-N-benzoyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoic acid (FCE29584), m.p. 175° C. dec.

¹H-NMR (200 MHz; d₆-DMSO) ppm: 3.52 (d, 2H); 4.85 (q, 1H); 7.30-7.58 (m,3H); 7.78-7.82 (m, 3H); 7.90-7.96 (m, 1H); 8.18 (s, 1H); 8.60 (d, 1H).

Microanalysis: calcd. for C₁₇H₁₄Cl₂NO₄: C 55.76; H 3.58; N 3.82; Cl19.36.

found: 53.71; 3.53; 3.70; 20.57.

(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′-chlorophenyl)-butanoic acid;and

(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′-fluorophenyl)-butanoic acid.

EXAMPLE 4(R,S)-N-methylsulfonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoicacid (FCE 29581)

To a solution of(R,S)-methyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoatehydrochloride (1.0 g, 3.2 mmol) in dry chloroform (50 ml), cooled at−10° C. and under dry nitrogen atmosphere, triethylamine (0.9 ml, 6.4mmol) dissolved in dry chloroform (10 ml) was slowly dropped in, keepingthe temperature below 0° C. To the stirred resulting suspension, asolution of mesylchloride (0.36 ml,3.3 mmol ) in dry chloroform (10 ml)was added during 15 min., on cooling at 0° C. The resulting yellowreaction mixture was stirred at room temperature further 30 min., andthen washed with ice cooled saturated sodium bicarbonate solution, 0.5 Nhydrochloric acid solution and then with brine, dried (Na₂SO₄) andevaporated under reduced pressure.

The resulting crude material was recrystallised from ethyl ether/hexaneto yield(R,S)-methyl-N-methylsulfonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoateas colourless needles (g 0.98, 89%), melting at 126-127° C.

¹H-NMR (200 MHz; d₆-DMSO) ppm: 2.98 (s, 3H); 3.52 (d, 2H); 3.66 (s, 3H);4.48 (q, 1H); 7.70 (d, 1H); 7.80 (d, 1H); 7.92 (dd, 1H); 8.15 (d, 1H).

To a solution of the above(R,S)-methyl-N-methylsulfonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoate(300 mg, 0.84 mmol) in 95% ethanol (20 ml), cooled at 0° C., 1N aqueoussodium hydroxyde solution (1.7 ml, 1.7 mmol) was added.

The resulting reaction mixture was stirred at 0° C. for 3 hours, thenneutralised with glacial acetic acid, the most of ethanol was evaporatedunder reduced pressure, and the residue taken up with ethyl acetate (50ml), washed with 0.5 N hydrochloric acid and then with brine, dried(Na₂SO₄), and evaporated under reduced pressure.

The resulting light yellow solid was recrystallised twice from ethylether to provide the pure titled acid as colourless needles (184 mg,65%), melting at 219° C.

¹H-NMR (200 MHz; d₆-DMSO) ppm: 2.96 (s, 3H); 3.45 (d, 2H); 4.38 (q, 1H);7.56 (d, 1H); 7.80-7.95 (m, 2H); 8.08 (s, 1H); 12.95 (broad s, 1H)

MS (FAB⁻; m/z): 338.3 (80; M+H⁻); 243.0 (100)

Microanalysis:

calcd. for C₁₁H₁₁Cl₂NO₅S: C 38.86; H 3.26; N 4.12; S 9.41; Cl 20.88.

found: 39.51; 3.53; 4.14; 9.33; 20.85.

EXAMPLE 5(R,S)-methyl-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoate

(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoicacid (1.0 g, 2.8 mmol) dissolved in dry methanol (30 ml) was treated atroom temperature with 6N methanolic solution of hydrochloric acid (0.9ml). The resulting solution was warmed on stirring at 40° C. for 4 hrs.,then the solvent was distilled off in vacuum, and the residue was takenup with ethyl ether (100 ml); the organic phase was washed with aqueoussodium bicarbonate, then with brine, dried (Na₂SO₄), and evaporatedunder reduced pressure.

The resulting oily material was crystallised with hexane/isopropyl etherto provide the pure titled compound as colourless solid (0.98 g; 96%),melting at 97-98° C.

¹H-NMR (200 MHz; CDCl₃) ppm: 3.55 (dd, 1H); 3.81 (s, 3H); 3.87 (dd, 1H); 4.96 (m , 1H); 7.43 (d, 1H); 7.58 (d, 1H); 7.75 (dd, 1H); 8.0 (d,1H).

MS (EI; m/z): 371 (4); 339 (18); 173 (100).

Microanalysis: calcd. for C₁₃H₁₀Cl₂ F₃NO₄: C 41.96; H 2.71; N 3.76; Cl19.05.

found: 41.83; 2.76; 3.56; 21.03.

EXAMPLE 6

Capsules, each weighing 0.23 g and containing 50 mg of the activesubstance can be prepared as follows:

Composition for 500 capsules:

(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′- 25 gdichlorophenyl)butanoic acid Lactose 80 g Corn starch  5 g Magnesiumstearate  5 g

This formulation can be incapsulated in two hard gelatin capsules of twopieces, each with each capsule weighing 0.23 g.

EXAMPLE 7

Intramuscular injection of 50 mg/ml

A pharmaceutical injectable composition can be manifactured dissolving50 g of

(R,S)-N-trifluoroacetyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoicacid in sterile propyleneglycol (1000 ml) and sealed in 1-5 ml ampoules.

Legend to FIG. 1, which shows kynurenine pathway

IDO: Indolamineoxygenase

TDO: Tryptophanedioxygenase

KYN: Kynurenine

KYN-3-OHase: Kynurenine-3-hydroxylase

KYN-3-OH: 3-Hydroxy kynurenine

KAT: Kynurenine amino transferase

3-OHAA: 3-Hydroxy anthranilic acid

KYNase: Kynureninase

3-HAO: 3-Hydroxy anthranilic acid dioxygenase

KYNA: Kynurenic acid

QUIN: Quinolinic acid

What is claimed is:
 1. A compound of the formula (Ia)

wherein each of the groups X and Y is, independently, hydrogen; halogen;nitro; C₁-C₆ alkyl; C₂-C₄ alkenyl; C₂-C₄ alkynyl; C₁-C₆ alkoxy; C₁-C₆alkylthio; SOR₂ or SO₂R₂ in which R₂ is C₁-C₆ alkyl, phenyl or benzyl;or SO₂N(R₃)₂ in which each of the groups R₃ is, independently, hydrogen,C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, phenyl or benzyl; R ishydroxy; —OR₅ in which R₅ is C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynylor benzyl; —N(R₃)₂ or —N(R₃)OR₃ in which each of R₃ is as defined above;W is —SO₂R₄ in which R₄ is C₁-C₆ alkyl, an optionally substituted C₂-C₄alkenyl, an optionally substituted phenyl or benzyl; —CONHR₅ or —CSNHR₅in which R₅ is as defined above; or a pharmaceutically acceptable saltthereof.
 2. The compound of the formula (Ia) according to claim 1wherein W is SO₂R₄ in which R₄ is C₁-C₄ alkyl and X and Y, which may bethe same or different are hydrogen or halogen, or a pharmaceuticallyacceptable salt thereof.
 3. The compound of the formula (Ia) accordingto claim 1 which isN-methylsulphonyl-2-amino-4-oxo-4-(3′,4′-dichlorophenyl)butanoic acid,either as single enantiomer or as a mixture thereof, or apharmaceutically acceptable salt thereof.
 4. A method of inhibitingkynurenine-3-hydroxylase enzyme in a mammal in need thereof, comprisingadministering to said mammal a kynurenine-3-hydroxylaseenzyme-inhibiting effective amount of a compound of formula (I) asdefined in claim 1, or a pharmaceutically acceptable salt thereof.
 5. Apharmaceutical composition for inhibiting kynurenine-3-hydroxylase,which comprises, as an active ingredient, an effective amount of one ormore compounds of the formula (I) of claim 1, or a pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable carrier.
 6. A pharmaceutical composition for inhibitingkynurenine-3-hydroxylase, which comprises, as an active ingredient, aneffective amount of one or more compounds of the formula (Ia) of claim1, or a pharmaceutically acceptable salt thereof, in association with apharmaceutically acceptable carrier.
 7. The method of claim 4, whereinsaid mammal is a human.